A ripk2 inhibitor compound, pharmaceutical composition and use thereof

Abstract

The application discloses a composition and a preparation method of a ripretinib cream, and the composition comprises: an active ingredient of ripretinib or a pharmaceutically acceptable salt thereof and excipients, wherein the excipients are composed of an oily base, a humectant, an emulsifier, water, a thickening agent, a preservative and a chelating agent, etc. The ripretinib cream composition disclosed by the application has the advantages of simpler preparation process, fewer excipients, smaller liquid drop particle size of the produced cream, no precipitation of the raw material drug in the use process, and equivalent clinical curative effect to the original Opzelura TM . The ripretinib cream composition disclosed by the application has the advantages of simpler preparation process, fewer excipients, smaller liquid drop particle size of the produced cream, no precipitation of the raw material drug in the use process, and equivalent clinical curative effect to the original Opzelura TM .

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a ruxolitinib cream composition, its preparation method, and its uses. Background Technology

[0002] Ruxolitinib cream (Opzelura™) is the first and only FDA-approved topical Janus kinase (JAK) inhibitor for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in adolescents (≥12 years of age) and adults who are not immunocompromised and whose condition has not been adequately controlled by topical prescription therapy or when such therapy is not advisable. It is also indicated for the topical treatment of non-segmental vitiligo in patients 12 years of age and older. To date, ruxolitinib cream is the first and only vitiligo repigmentation treatment approved for use in the United States.

[0003] Vitiligo is a chronic autoimmune disease characterized by the loss of skin pigmentation, caused by the absence of melanocytes, the cells that produce pigment. It is estimated that there are approximately 14 million vitiligo patients in China. About 85% of vitiligo patients have non-segmental vitiligo. Topical corticosteroids (TCS) and calcineurin inhibitors (CI) are the label medications for non-segmental vitiligo; however, these existing topical therapies have clinical drawbacks such as adverse reactions from long-term use or limited efficacy. Ruxolitinib cream will bring new hope to the vast number of vitiligo patients in China.

[0004] Atopic dermatitis (AD) is a chronic, relapsing, itchy, inflammatory skin disease that severely impacts the quality of life for patients and their families. This disease is related to genetic allergies and is often accompanied by impaired skin barrier function. It typically begins in infancy. Data shows that approximately 50% of cases occur before the age of one. The disease has a chronic course, and in some patients, the condition may persist into adulthood. Currently, the incidence of AD in developed countries can be as high as 10%-20%. Epidemiological surveys in my country also show an increasing trend in the incidence of this disease. For example, a 2000 epidemiological survey in my country showed a total prevalence of 0.70% among school-aged adolescents (6-20 years old). In 2004, the prevalence among urban preschool children (1-7 years old) was 2.78%. Generally, the incidence of AD decreases with age, and the condition gradually improves. It is worth mentioning that Opzelura... TM It is the first and only topical Janus kinase (JAK) inhibitor approved by the US FDA. Studies have shown that dysregulation of the JAK-STAT pathway leads to key features of Alzheimer's disease (AD), such as itching, inflammation, and impaired skin barrier function. In a Phase III clinical trial, ruxolitinib cream treatment significantly reduced AD-related skin inflammation and itching, and reduced itching may potentially improve key disease-related and quality-of-life outcomes in AD patients.

[0005] Currently available ruxolitinib cream (Opzelura) TM The preparation process involved is complex. For example, high-frequency homogenization is required during the high-temperature emulsification stage, and low-frequency homogenization is required during the cooling process. At the same time, the finished product droplet size is relatively large, which may cause problems such as the precipitation of raw materials during use. Summary of the Invention

[0006] The purpose of this invention is to provide a ruxolitinib cream composition and its preparation method.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] This invention relates to a ruxolitinib cream composition and its preparation method, characterized in that the ruxolitinib cream is composed of ruxolitinib or its pharmaceutically acceptable salt active ingredient and excipients, wherein the excipients are composed of an oil phase matrix, a humectant, an emulsifier, a solvent, a thickener, water, a preservative, and a chelating agent.

[0009] As one embodiment, the active ingredients and excipients, by mass percentage of the total weight of ruxolitinib cream, comprise: ruxolitinib phosphate 0.5-5% (0.38-3.8% based on ruxolitinib free base), oil phase matrix 8-18%, humectant 5-18%, emulsifier 3-6%, solvent 8-15%, thickener 0.2-0.5%, preservative 0.05-0.5%, chelating agent 0.025-0.075%, and water 40-65%.

[0010] As one embodiment, the emulsifier is polysorbate and polyoxyethylene stearate.

[0011] As one embodiment, the emulsifier is polysorbate 60 and polyoxyethylene (32) stearate, with polysorbate 60 accounting for 1-2% and polyoxyethylene (32) stearate accounting for 2-4% of the total weight of ruxolitinib cream, and the mass ratio of polysorbate 60 to polyoxyethylene (32) stearate is 1:1-1:4.

[0012] As one implementation, the thickener is Sepineo. TM P600, based on the percentage of ruxolitinib cream by weight, contains 0.2-0.5% thickener.

[0013] As one embodiment, the solvent is PPG-15 stearyl alcohol ether, accounting for 8-15% of the total weight of ruxolitinib cream by mass.

[0014] As one implementation, the oil phase matrix is ​​selected from any one or more of medium-chain triglycerides, cetyl alcohol, octadecanol, and light liquid paraffin. As a preferred embodiment, the oil phase matrix is ​​medium-chain triglycerides, cetyl alcohol, and octadecanol.

[0015] As one implementation, the humectant is selected from any one or more of propylene glycol, glycerin, 1,3-butanediol, methyl glucono-polyether 10, and methyl glucono-polyether 20. As a preferred embodiment, the humectant is propylene glycol, glycerin, or methyl glucono-polyether 10. As another preferred embodiment, the humectant is 1,3-butanediol, glycerin, or propylene glycol.

[0016] As one implementation scheme, the preservatives are methylparaben and propylparaben, and the chelating agent is disodium edetate.

[0017] As one implementation, the active ingredients and excipients, by weight percentage of the total weight of ruxolitinib cream, comprise: ruxolitinib phosphate 0.5-5% (0.38-3.8% based on ruxolitinib free base), oil phase matrix 8-18%, humectant 5-18%, emulsifier 3-6%, solvent 8-15%, thickener 0.2-0.5%, preservative 0.05-0.5%, chelating agent 0.025-0.075%, and water 40-65%. The emulsifier is polysorbate 60 and polyoxyethylene (32) stearate, and the thickener is Sepineo... TM P600, the solvent is PPG-15 stearyl alcohol ether.

[0018] As one embodiment, the ruxolitinib cream of the present invention has the following raw materials, excipients, and formulation proportions (in percentage by mass of the total weight of the ruxolitinib cream):

[0019] Table 1

[0020]

[0021] This invention also relates to a method for preparing ruxolitinib cream, the method comprising the following steps:

[0022] (1) Preparation of aqueous phase: Take the prescribed amount of water, add emulsifier polysorbate 60, humectant, chelating agent and preservative, heat to 70-75℃ and stir to dissolve.

[0023] (2) Preparation of oil phase: Take the prescribed amount of emulsifier polyoxyethylene (32) stearate, oil phase matrix and solvent, heat to 70-75℃ and stir to dissolve.

[0024] (3) Preparation of the active phase: The active drug ruxolitinib phosphate is introduced into step (1) and stirred to dissolve.

[0025] (4) Add the thickener to step (3) and stir.

[0026] (5) Emulsification: Add the oil phase to step (4), stir, and homogenize.

[0027] (6) Filling: Cool the homogenized cream to room temperature and fill it into aluminum tubes to obtain ruxolitinib cream.

[0028] This invention also relates to the use of ruxolitinib cream as a topical medication for the treatment of atopic dermatitis, psoriasis, vitiligo, urticaria, alopecia areata, etc.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The ruxolitinib cream of this invention has a simpler preparation process, requires fewer excipients, and eliminates the need for different formulation tanks during production. Furthermore, it eliminates the need for high-frequency homogenization during the high-temperature emulsification stage and low-frequency homogenization during the cooling process. The cream prepared according to the formulation of this invention has a smaller droplet size than the commercially available ruxolitinib cream Opzelura™, resulting in higher stability. No drug substance precipitation occurs during use, and it exhibits equivalent clinical efficacy to the original Opzelura™. Attached Figure Description

[0031] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0032] Figure 1 Example 1: Appearance of the cream;

[0033] Figure 2 Example 1: Microscopic observation of the cream;

[0034] Figure 3 Example 1: Microscopic observation of the cream after opening;

[0035] Figure 4 Example 1: Centrifugal stratification;

[0036] Figure 5 Comparative Example 5: Cream appearance image;

[0037] Figure 6 Comparative Example 5: Microscopic observation;

[0038] Figure 7 Comparative Example 5: Microscopic observation after opening;

[0039] Figure 8 Comparative Example 5: Centrifugation and Layering;

[0040] Figure 9 Comparative Example 4: Microscopic observation of the cream; Detailed Implementation

[0041] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention. The proportions in the table below are all percentages of the total weight of ruxolitinib cream.

[0042] The preparation method of the ruxolitinib cream of the present invention includes the following steps:

[0043] (1) Preparation of aqueous phase: Take the prescribed amount of water, add emulsifier polysorbate 60, humectant, chelating agent and preservative, heat to 70-75℃ and stir to dissolve.

[0044] (2) Preparation of oil phase: Take the prescribed amount of emulsifier polyoxyethylene (32) stearate, oil phase matrix and solvent, heat to 70-75℃ and stir to dissolve.

[0045] (3) Preparation of the active phase: Add the active drug ruxolitinib phosphate to step (1) and stir to dissolve.

[0046] (4) Add the thickener to step (3) and stir.

[0047] (5) Emulsification: Add the oil phase to step (4), stir, and homogenize.

[0048] 6) Filling: After homogenization, cool the cream to room temperature and fill it into aluminum tubes to obtain ruxolitinib cream.

[0049] Specific application examples are as follows:

[0050] Examples 1-5

[0051] Table 2

[0052]

[0053]

[0054] Comparative Examples 1-2, Table 3

[0055]

[0056]

[0057] Preparation of the control formulation in Comparative Example 4

[0058] A cream containing ruxolitinib was prepared as a control formulation according to the formulation in Table 5, paragraph 0274, on page 26 of the specification of patent application number 201180035301.2 and the preparation process in paragraphs 0277-0286 of the specification. The raw materials and their proportions are shown in Table 4 below.

[0059] Table 4

[0060]

[0061]

[0062] The preparation process of ruxolitinib cream is as follows:

[0063] 1. A paraben phase is prepared by mixing methylparaben and propylparaben with 5% propylene glycol according to the formulation.

[0064] 2. Next, xanthan gum phase is prepared by mixing xanthan gum and propylene glycol;

[0065] 3. The oil phase is then prepared by mixing light mineral oil, glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, stearyl alcohol, dimethylsiloxane, and medium-chain triglycerides. This phase is heated to 70-80°C until it melts and forms a homogeneous mixture.

[0066] 4. Next, an aqueous phase is prepared by mixing purified water, polyethylene glycol, and disodium EDTA. This phase is then heated to 70-80℃.

[0067] 5. Combine the aqueous phase from step 4, the p-hydroxybenzoate phase from step 1, and ruxolitinib phosphate to form a mixture;

[0068] 6. Then the xanthan gum phase from step 2 is added to the mixture from step 5;

[0069] 7. Then, under high-shear mixing, the oil phase from step 3 and the mixture from step 6 are combined to form an emulsion;

[0070] 8. Then, phenoxyethanol is added to the emulsion from step 7, and mixing continues. The product is then cooled under low-shear mixing.

[0071] Comparative Example 5: Commercially available ruxolitinib cream (Opzelura) TM ).

[0072] Example 6: Quality Comparison Study

[0073] The properties, viscosity, pH, content, related substances, and content uniformity of Example 1 and Comparative Examples 1-5 were tested. Long-term stability of Example 1 and Comparative Example 5 was investigated (stored at 25℃±2℃, 60%RH±5%RH), and the results are shown in Table 5 below.

[0074] Table 5

[0075]

[0076]

[0077] Conclusion: After 6 months of stability, the viscosity of the cream prepared according to Example 1 of this patent remained relatively stable, showing no significant difference compared to day 0, while the viscosity of the cream in Comparative Example 5 showed a slight decreasing trend. This indicates that the cream prepared in Example 1 has significantly better stability than that in Comparative Example 5.

[0078] A quality comparison between the cream prepared according to Comparative Example 4 and Comparative Example 5 of this patent shows that the creams prepared according to Comparative Example 4 and Comparative Example 5 have essentially the same quality. This indicates that the original drug's ruxolitinib cream, prepared according to the formulation in Table 5, paragraph 0274 on page 26 of the specification of patent application number 201180035301.2 and the preparation process in paragraphs 0277-0286 of the specification, has a complex formulation process, requiring different formulation tanks to meet the formulation requirements during production. Furthermore, high-frequency homogenization is required during the high-temperature (70-80℃) emulsification stage, and low-frequency homogenization is required during the cooling process. This indicates that the cream is prone to droplet size enlargement or even emulsification during cooling, thus requiring low-frequency homogenization during cooling to ensure the stability of the cream during the cooling process. The droplet size distribution of the finished cream prepared according to Comparative Example 4 of this patent is uneven, and there are large droplet sizes that are essentially the same as those in Comparative Example 5. See details... Figure 9 .

[0079] Comparative Example 2, without the addition of a thickener, has a viscosity much lower than that of Example 1 and Comparative Example 5, resulting in a more fluid cream that flows easily when applied. Therefore, no other test indicators were examined.

[0080] Example 7 Microscopic observation

[0081] Both Example 1 and Comparative Example 5 are oil-in-water emulsions. The droplet size of the emulsion affects the quality and performance of the drug. Since emulsions are inherently thermodynamically unstable, droplet size and its distribution are key test items for monitoring the stability of emulsion products.

[0082] Examples 1 and 5 were observed under a microscope:

[0083] Take freshly opened samples of Example 1 and Comparative Example 5; the results of specific microscopic observations are shown in [the original text]. Figure 2and Figure 6 After the simulation was activated and the sample was left at room temperature for 3 months, it was observed under a microscope again. See details below. Figure 3 and Figure 7 .

[0084] Results Analysis: The droplet size in Example 1 was significantly smaller than that in Comparative Example 5, and the droplet size distribution in Example 1 was uniform, with D90 ≤ 10 μm. Comparative Example 5 showed obvious droplet aggregation, and the droplet size distribution was uneven, with D90 ≤ 30 μm. From... Figure 7 It can be seen that in Comparative Example 5, after the simulation was started and left at room temperature for 3 months, significant precipitation of the active pharmaceutical ingredient (API) occurred, and the droplet size showed signs of demulsification. Meanwhile, in Example 1, after the simulation was started for 3 months, no API precipitation was observed, and the droplet size did not change significantly.

[0085] Results analysis: The droplet size of the formula prepared according to Example 1 was significantly better than that of Comparative Example 5, indicating that the stability of the cream in Example 1 was significantly better than that in Comparative Example 5.

[0086] Example 8 Centrifugation Study

[0087] Instrument: Benchtop high-speed refrigerated centrifuge, model: TGL-16.5M

[0088] Centrifugation parameters: 10000 rpm, 20 min

[0089] Example 1 and Comparative Example 5 were subjected to high-speed centrifugation. Specific centrifugation results are shown in [link to results]. Figure 4 and Figure 8 .

[0090] Results analysis: The cream prepared according to Example 1 of this patent showed significantly less centrifugal separation than Comparative Example 5, indicating that the product stability of Example 1 is better than that of Comparative Example 5.

[0091] Example 9: In vitro transdermal test (IVPT) study

[0092] 1) Method: Franz diffusion cell method;

[0093] 2) Instrument: LOGAN 918-12 system, LOGAN transdermal diffusion assay apparatus.

[0094] 3) Skin: The experimental material was Bama fragrant pig skin, with a thickness of 0.5±0.1mm and a contact diameter of 1.767cm2;

[0095] 4) Receiving solution: physiological saline;

[0096] 5) Receiving liquid temperature: 32±0.5℃;

[0097] 6) Rotation speed: 600 rpm;

[0098] 7) Samples: The different formulations were evenly coated on the experimental pigskin, with each formulation having a sample size of about 15 mg. Pigskin without cream was used as blank pigskin.

[0099] 8) Diffusion cell volume: 12ml;

[0100] 9) Sampling method: Sampling all samples;

[0101] 10) Sampling time points: 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 20h, 24h;

[0102] 11) Sample analysis: HPLC determination, the results are shown in Table 4.

[0103] Table 6

[0104]

[0105] Results analysis: The ruxolitinib cream prepared according to Examples 1-5 had the same intradermal retention as Comparative Example 4 (cream prepared according to the original patent) and Comparative Example 5 (reference preparation), and was significantly higher than that of Comparative Example 1, indicating that Examples 1-5 and the reference preparation have similar clinical efficacy.

[0106] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A ruxolitinib cream composition, characterized in that, The ruxolitinib cream composition comprises ruxolitinib or a pharmaceutically acceptable salt thereof as its active ingredient and excipients, wherein the excipients consist of an oil phase matrix, a humectant, a thickener, a solvent, an emulsifier, water, a preservative, and a chelating agent, and the ruxolitinib cream is a solution-type oil-in-water cream.

2. The ruxolitinib cream composition according to claim 1, characterized in that, The active ingredients and excipients, by weight percentage of the total weight of ruxolitinib cream, are: ruxolitinib phosphate 0.5-5% (0.38-3.8% based on ruxolitinib free base), oil phase matrix 8-18%, humectant 5-18%, emulsifier 3-6%, solvent 8-15%, thickener 0.2-0.5%, preservative 0.05-0.5%, chelating agent 0.025-0.075%, and water 40-65%.

3. The ruxolitinib cream composition according to claim 1, characterized in that, The emulsifiers are polysorbate and polyoxyethylene stearate.

4. The ruxolitinib cream composition according to claim 3, characterized in that, The emulsifier is polysorbate 60 and polyoxyethylene (32) stearate. Based on the mass percentage of the total weight of ruxolitinib cream, polysorbate 60 accounts for 1-2%, polyoxyethylene (32) stearate accounts for 2-4%, and the mass ratio of polysorbate 60 to polyoxyethylene (32) stearate is 1:1-1:

4.

5. The ruxolitinib cream composition according to claim 1, characterized in that, The thickener is Sepineo. TM P600, based on the percentage of ruxolitinib cream by weight, contains 0.2-0.5% thickener.

6. The ruxolitinib cream composition according to claim 1, characterized in that, The solvent is PPG-15 stearyl ether, and its percentage by weight of the total weight of ruxolitinib cream is 8-15%.

7. The ruxolitinib cream composition according to claim 1, characterized in that, The oil phase matrix is ​​selected from any one or more of medium-chain triglycerides, cetyl alcohol, octadecanol, and light liquid paraffin, and the oil phase matrix accounts for 8-18% of the total weight of ruxolitinib cream.

8. The ruxolitinib cream composition according to claim 1, characterized in that, The moisturizer is selected from any one or more of propylene glycol, glycerin, 1,3-butanediol, methyl gluconol 10, and methyl gluconol 20, and the moisturizer accounts for 5-18% of the total weight of ruxolitinib cream.

9. The ruxolitinib cream composition according to claim 1, characterized in that, The active ingredients and excipients, by weight percentage of the total weight of ruxolitinib cream, are as follows: ruxolitinib phosphate 0.5-5% (0.38-3.8% based on ruxolitinib free base), oil phase matrix 8-18%, humectant 5-18%, emulsifier 3-6%, solvent 8-15%, thickener 0.2-0.5%, preservative 0.05-0.5%, chelating agent 0.025-0.075%, and water 40-65%. The emulsifier is polysorbate 60 and polyoxyethylene (32) stearate, and the thickener is Sepineo... TM P600, the solvent is PPG-15 stearyl alcohol ether.

10. The method for preparing the ruxolitinib cream composition according to claim 1, characterized in that, It includes the following steps: (1) Preparation of aqueous phase: Take the prescribed amount of water, add emulsifier polysorbate 60, humectant, chelating agent and preservative, heat to 70-75℃ and stir to dissolve; (2) Preparation of oil phase: Take the prescribed amount of emulsifier polyoxyethylene (32) stearate, solvent and oil phase matrix, heat to 70-75℃ and stir to dissolve; (3) Preparation of the active phase: The active drug ruxolitinib phosphate is introduced into step (1) and stirred to dissolve; (4) Add the thickener to step (3) and stir; (5) Emulsification: Add the oil phase to step (4), stir, and homogenize; (6) Filling: Cool the homogenized cream to room temperature and fill it into aluminum tubes to obtain ruxolitinib cream.

11. The use of ruxolitinib cream according to any one of claims 1-10 for the treatment of diseases, wherein the diseases are one or more of atopic dermatitis, psoriasis, vitiligo, urticaria, and alopecia areata.

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